Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:13][N:12]=[C:11]([C:14]3[CH:15]=[C:16]([CH:21]=[CH:22][CH:23]=3)[C:17]([O:19]C)=[O:18])[CH:10]=2)=[CH:5][CH:4]=1.[OH-].[Na+].O1CCCC1.Cl>O.CO>[F:25][C:2]([F:1])([F:24])[C:3]1[CH:4]=[CH:5][C:6]([C:9]2[O:13][N:12]=[C:11]([C:14]3[CH:15]=[C:16]([CH:21]=[CH:22][CH:23]=3)[C:17]([OH:19])=[O:18])[CH:10]=2)=[CH:7][CH:8]=1
Reactant: COC(=O)c1cccc(-c2cc(-c3ccc(C(F)(F)F)cc3)on2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1cccc(-c2cc(-c3ccc(C(F)(F)F)cc3)on2)c1
Temperature: 60 °C
Reaction time: 1 h
Yield: 87.8 %

Procedure:
A mixture of methyl 3-[5-(4-trifluoromethylphenyl)-3-isoxazolyl]benzoate (1.04 g), 1 M aqueous sodium hydroxide solution (10 ml), tetrahydrofuran (30 ml) and methanol (30 ml) was stirred at 60° C. for 1 hr. After cooling, the reaction mixture was poured into water, and 1 M hydrochloric acid (20 ml) was added. The crystals were collected by filtration and recrystallized from ethanol to give 3-[5-(4-trifluoromethylphenyl)-3-isoxazolyl]benzoic acid (0.876 g, yield 88%) as a colorless crystalline powder. melting point: 276–277° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][C:9](B(O)O)=[CH:10]2)=[CH:5][CH:4]=1.[Cl:16][C:17]1[CH:18]=[C:19]([CH2:23][N:24]2[CH:28]=[CH:27][N:26]=[C:25]2[CH3:29])[N:20]=[N:21][CH:22]=1>>[ClH:16].[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][C:9]([C:17]3[CH:18]=[C:19]([CH2:23][N:24]4[CH:28]=[CH:27][N:26]=[C:25]4[CH3:29])[N:20]=[N:21][CH:22]=3)=[CH:10]2)=[CH:5][CH:4]=1
Reactant: Cc1nccn1Cc1cc(Cl)cnn1
Reactant: COc1ccc2c(c1)C=C(B(O)O)CC2
Product: COc1ccc2c(c1)C=C(c1cnnc(Cn3ccnc3C)c1)CC2
Product: Cl

Procedure:
The title compound, MS: m/e=333.3 (M+H+), was prepared from 7-methoxy-3,4-dihydro-naphthalene-2-boronic acid and 5-chloro-3-(2-methyl-imidazol-1-yl-methyl)-pyridazine.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5](=[O:11])[C:6]([CH3:10])([CH3:9])[CH2:7][OH:8].[CH3:12]OS(C1C=CC(C)=CC=1)(=O)=O>CN(C)C=O.O.CCCCCC>[CH3:3][O:4][C:5](=[O:11])[C:6]([CH3:10])([CH3:9])[CH2:7][O:8][CH3:12]
Reactant: COS(=O)(=O)c1ccc(C)cc1
Reactant: COC(=O)C(C)(C)CO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCCCCC
Product: COCC(C)(C)C(=O)OC
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 55 %

Procedure:
1 mol of sodium hydride was added to the solvent dimethylformamide, and 1 mol of hydroxypivalic acid methyl ester was added thereto while the temperature of the solution did not exceed 30° C. The solution was stirred at room temperature for 90 minutes. Then, 1.2 mol of p-toluenesulfonic acid methyl ester was added to the solution while the temperature of the solution did not exceed 30° C. Then, a water/hexane mixture having the same mass as that of the dimethylformamide was added to the solution, which was then stirred, after which water was removed therefrom. The resulting organic material was concentrated, and the residue was fractionated at 700 Pa and 93° C., thereby obtaining the intermediate 3-methoxy-2,2-dimethylpropionic acid methyl ester at a yield of 55%.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:19])=[C:4]([O:8][C:9](=[O:18])[NH:10][CH2:11][C@@H:12]2[CH2:17][C@@H:16]3[C@@H:14]([CH2:15]3)[NH:13]2)[CH:5]=[CH:6][CH:7]=1.ClC1C(F)=C(OC(=O)NC[C@@H]2C[C@@H]3[C@@H](C3)N2C(=O)NC2C3C(=CC=CC=3)N(C(=O)N)C=2)C=CC=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[C:87]([C:90]1[C:98]2[C:93](=[CH:94][CH:95]=[CH:96][CH:97]=2)[N:92]([CH2:99][C:100](O)=[O:101])[CH:91]=1)(=[O:89])[CH3:88]>C1COCC1>[Cl:1][C:2]1[C:3]([F:19])=[C:4]([O:8][C:9](=[O:18])[NH:10][CH2:11][C@@H:12]2[CH2:17][C@@H:16]3[C@@H:14]([CH2:15]3)[N:13]2[C:100](=[O:101])[CH2:99][N:92]2[C:93]3[C:98](=[CH:97][CH:96]=[CH:95][CH:94]=3)[C:90]([C:87](=[O:89])[CH3:88])=[CH:91]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)c1cn(CC(=O)O)c2ccccc12
Reactant: O=C(NC[C@@H]1C[C@H]2C[C@H]2N1)Oc1cccc(Cl)c1F
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: NC(=O)n1cc(NC(=O)N2[C@H](CNC(=O)Oc3cccc(Cl)c3F)C[C@H]3C[C@H]32)c2ccccc21
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)c1cn(CC(=O)N2[C@H](CNC(=O)Oc3cccc(Cl)c3F)C[C@H]3C[C@H]32)c2ccccc12
Temperature: 25 °C
Reaction time: 60 h

Procedure:
To a solution of [(1R,3S,5R)-1-(2-aza-bicyclo[3.1.0]hex-3-yl)methyl]-carbamic acid 3-chloro-2-fluoro-phenyl ester, trifluoroacetate (prepared as described in Example 115) (60.0 mg, 0.211 mmol) in THF (3 mL) was added HBTU (120 mg, 0.316 mmol), DIPEA (0.147 mL, 0.843 mmol) and (3-acetyl-indol-1-yl)-acetic acid (50 mg, 0.232 mmol). The reaction mixture was stirred at RT for 60 h. Volatiles were removed under reduced pressure and the residue was purified by preparative HPLC (Waters Sunfire, C18-ODB, 5 μm, 30×100 mm, eluent: 20-100% CH3CN/H2O/20 min, 100% CH3CN/2 min, CH3CN and H2O containing 0.1% TFA, flow: 40 mL/min) to give after lyophilization of the purified HPLC fractions the title compound. MS (LC/MS): 484.0 [M+H]+; tR (HPLC conditions k): 3.69 min.
Reaction SMILES: [CH2:1]([N:8]1[C@@H:13]2[C@H:14]([C:16]#[N:17])[CH2:15][C@@:9]1([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C@H:10]([O:18][CH2:19][C:20]1[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[C:22]([C:30]([F:33])([F:32])[F:31])[CH:21]=1)[CH2:11][CH2:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N-:40]=[N+:41]=[N-:42].[Na+].[Cl-].[NH4+].O>CN(C)C=O>[CH2:1]([N:8]1[C@@H:13]2[C@H:14]([C:16]3[NH:42][N:41]=[N:40][N:17]=3)[CH2:15][C@@:9]1([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C@H:10]([O:18][CH2:19][C:20]1[CH:25]=[C:24]([C:26]([F:28])([F:29])[F:27])[CH:23]=[C:22]([C:30]([F:31])([F:32])[F:33])[CH:21]=1)[CH2:11][CH2:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#C[C@@H]1C[C@@]2(c3ccccc3)[C@H](OCc3cc(C(F)(F)F)cc(C(F)(F)F)c3)CC[C@@H]1N2Cc1ccccc1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: FC(F)(F)c1cc(CO[C@@H]2CC[C@H]3[C@H](c4nnn[nH]4)C[C@]2(c2ccccc2)N3Cc2ccccc2)cc(C(F)(F)F)c1
Temperature: 25 °C
Yield: 62.1 %

Procedure:
(1R*,2R*,5S*,6R*)-8-Benzyl-2-{[3,5-bis(trifluoromethyl)phenyl]methoxy}-6-cyano-1-phenyl-8-azabicyclo[3.2.1]octane (Example 137; 4 g, 7.4 mmol), sodium azide (1.4 g, 22 mmol) and ammonium chloride (1.2 g, 22 mmol) were stirred at 120° C. in N,N-dimethylformamide (15 ml) for 20 hours. On cooling to room temperature the mixture was poured into water (250 ml) and extracted (×2) with ethyl acetate. The combined organic extracts were washed (×3) with water then dried (MgSO4), filtered and concentrated. Residue was chromatographed on silica gel eluting with 1, 2 and 4% methanol/dichloromethane to give the title compound (2.7 g, 63%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:13])=[N:4][C:5]([C:9]([Cl:12])([Cl:11])[Cl:10])=[N:6][C:7]=1[CH3:8].C(N(CC)CC)C.[Cl:21][C:22]([Cl:27])([Cl:26])[C:23](Cl)=[O:24]>C(OCC)C>[Cl:1][C:2]1[C:3]([O:13][C:23](=[O:24])[C:22]([Cl:27])([Cl:26])[Cl:21])=[N:4][C:5]([C:9]([Cl:10])([Cl:11])[Cl:12])=[N:6][C:7]=1[CH3:8]
Reactant: Cc1nc(C(Cl)(Cl)Cl)nc(O)c1Cl
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: Cc1nc(C(Cl)(Cl)Cl)nc(OC(=O)C(Cl)(Cl)Cl)c1Cl
Reaction time: 0.17 h
Yield: 35 %

Procedure:
To a solution of 5.8 g (0.02 mole) 5-chloro-4-hydroxy-6-methyl-2-trichloromethylpyrimidine and 2.0 g (0.02 mole) triethylamine in 100 ml diethyl ether was added 3.6 g (0.02 mole) trichloroacetyl chloride. After the exothermic reaction subsided, the reaction mixture was stirred an additional 10 minutes and filtered. The filtrate was concentrated in-vacuo and the residue recrystallized from ligroin to give 1.6 g starting material and 2.3 g product; m.p. 92° C. The corrected yield was 35%.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].CS([C:11]1[N:12]=[C:13]([O:30][CH:31]2[CH2:34][O:33][CH2:32]2)[C:14]2[N:19]=[C:18]([C:20]3[CH:25]=[C:24]([CH3:26])[C:23]([O:27][CH3:28])=[C:22]([CH3:29])[CH:21]=3)[O:17][C:15]=2[N:16]=1)(=O)=O.[F:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=1[OH:42]>CN(C=O)C>[F:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=1[O:42][C:11]1[N:12]=[C:13]([O:30][CH:31]2[CH2:34][O:33][CH2:32]2)[C:14]2[N:19]=[C:18]([C:20]3[CH:25]=[C:24]([CH3:26])[C:23]([O:27][CH3:28])=[C:22]([CH3:29])[CH:21]=3)[O:17][C:15]=2[N:16]=1
Reactant: COc1c(C)cc(-c2nc3c(OC4COC4)nc(S(C)(=O)=O)nc3o2)cc1C
Reactant: Oc1ccccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1c(C)cc(-c2nc3c(OC4COC4)nc(Oc4ccccc4F)nc3o2)cc1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 143.8 %

Procedure:
410 mg of potassium carbonate and 547 mg of 5-methanesulfonyl-2-(4-methoxy-3,5-dimethyl-phenyl)-7-(oxetan-3-yloxy)-oxazolo[5,4-d]pyrimidine were added to a solution of 49 mg of 2-fluorophenol in 8 ml of DMF. The mixture was stirred at room temperature for 2 h. After filtration, the solvent was distilled off in vacuo, and the product was isolated by silica gel chromatography (heptane/ethyl acetate gradient) to yield 275 mg of the title compound.
Reaction SMILES: [P:1]([O-:8])([O:5]CC)[O:2]CC.O.[CH2:10]([O:19][CH2:20][CH2:21][CH2:22][NH2:23])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH:16]([CH3:18])[CH3:17]>C(O)C>[CH2:10]([P:1](=[O:2])([O-:5])[O-:8])[CH3:11].[CH2:10]([O:19][CH2:20][CH2:21][CH2:22][NH3+:23])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH:16]([CH3:17])[CH3:18].[CH2:10]([O:19][CH2:20][CH2:21][CH2:22][NH3+:23])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH:16]([CH3:17])[CH3:18]
Reactant: CC(C)CCCCCCOCCCN
Reactant: CCOP([O-])OCC
Solvent: CCO
Solvent: O
Product: CC(C)CCCCCCOCCC[NH3+]
Product: CCP(=O)([O-])[O-]

Procedure:
A mixture of 13.81 g. (0.1 moles) of diethyl phosphite, 20 ml. of water and 20 ml. of ethanol is reacted with a mixture of 20.13 g. (0.1 moles) of 3-isononyloxypropyl amine and 30 ml. of ethanol as described in Example 1. nD30 =1.4485 (liquid fraction).
Reaction SMILES: F[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:11]=2[N:12]=1.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C.[F:32][C:33]([F:37])([F:36])[CH2:34][SH:35]>O>[F:32][C:33]([F:37])([F:36])[CH2:34][S:35][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:11]=2[N:12]=1
Reactant: Fc1cnccc1-c1nc2cc(C(F)(F)F)ccc2o1
Reactant: FC(F)(F)CS
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: FC(F)(F)CSc1cnccc1-c1nc2cc(C(F)(F)F)ccc2o1
Temperature: 25 °C
Reaction time: 1.2 h
Yield: 85.3 %

Procedure:
To a mixture of 0.28 g of 2-(3-fluoropyridin-4-yl)-5-(trifluoromethyl)benzoxazole, 0.50 g of potassium carbonate and 2 ml of DMF, 0.15 g of 2,2,2-trifluoroethanethiol was added. The reaction mixture was stirred at room temperature for 1.2 hours. Water was added to reaction mixture, which followed by extraction with ethyl acetate twice. The combined organic layers were washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 0.32 g of 2-[3-(2,2,2-trifluoroethylthio)pyridin-4-yl]-5-(trifluoromethyl)benzoxazole (hereinafter, referred to as “active compound 46”).
Reaction SMILES: [CH:1]([C@@H:4]([NH2:17])[CH2:5][O:6][CH2:7][CH:8]1[CH2:13][CH2:12][N:11]([CH:14]([CH3:16])[CH3:15])[CH2:10][CH2:9]1)([CH3:3])[CH3:2].[Cl:18][C:19]1[C:27]2[C:22](=[CH:23][C:24]([C:28](O)=[O:29])=[CH:25][CH:26]=2)[NH:21][CH:20]=1>>[ClH:18].[Cl:18][C:19]1[C:27]2[C:22](=[CH:23][C:24]([C:28]([NH:17][C@H:4]([CH:1]([CH3:3])[CH3:2])[CH2:5][O:6][CH2:7][CH:8]3[CH2:9][CH2:10][N:11]([CH:14]([CH3:16])[CH3:15])[CH2:12][CH2:13]3)=[O:29])=[CH:25][CH:26]=2)[NH:21][CH:20]=1
Reactant: CC(C)[C@@H](N)COCC1CCN(C(C)C)CC1
Reactant: O=C(O)c1ccc2c(Cl)c[nH]c2c1
Product: CC(C)[C@H](COCC1CCN(C(C)C)CC1)NC(=O)c1ccc2c(Cl)c[nH]c2c1
Product: Cl

Procedure:
Using coupling method A, (R)-1-(isopropyl)-2-(1-iso-propylpiperidin-4-ylmethoxy)ethylamine (135 mg, 0.56 mmol) and 3-chloroindole-6-carboxylic acid (109 mg, 0.56 mmol) afforded, after purification (SiO2: 4:2:1 DCM:EtOAc:isopropylamine) and conversion to the HCl salt by general method A, 167 mg (66%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:10]([C:23]#[N:24])=[C:11]([C:16]2[CH:21]=[CH:20][N:19]=[C:18]([F:22])[CH:17]=2)[S:12][C:13]=1[CH:14]=O.CO.[C:27](=O)([O-])[O-].[K+].[K+].[N+](=C(P(=O)(OC)OC)C(=O)C)=[N-]>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:10]([C:23]#[N:24])=[C:11]([C:16]2[CH:21]=[CH:20][N:19]=[C:18]([F:22])[CH:17]=2)[S:12][C:13]=1[C:14]#[CH:27]
Reactant: N#Cc1c(-c2ccnc(F)c2)sc(C=O)c1-c1ccc(Cl)cc1Cl
Reactant: O=C([O-])[O-]
Agent: COP(=O)(OC)C(=[N+]=[N-])C(C)=O
Agent: [K+]
Solvent: CO
Product: C#Cc1sc(-c2ccnc(F)c2)c(C#N)c1-c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 4-(2,4-dichlorophenyl)-2-(2-fluoropyridin-4-yl)-5-formylthiophene-3-carbonitrile (200.0 mg, 0.5302 mmol) in dry MeOH (12 mL, 3.0E2 mmol) was added Potassium carbonate (161 mg, 1.17 mmol) and dimethyl 1-diazo-2-oxopropylphosphonate (132 mg, 0.689 mmol). The mixture was stirred at rt for 2 h. The mixture was quenched by sodium bicarbonate solution and extracted with EtOAc. The organic layer was dried and evaporated. The residue was purified by column chromatography to afford the title compound. LC/MS (A) ES+ 373, 375. 1H NMR (400 MHz, d1-chloroform) δ: 8.39 (1H, d, J=5.29 Hz), 7.61 (2H, ddd, J=6.19, 3.83, 1.68 Hz), 7.45-7.31 (3H, m), 3.49 (1H, s)
Reaction SMILES: Br[C:2]1[C:3]([CH3:19])=[N:4][C:5]2[N:6]([N:9]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=3)[CH:11]=2)[C:7]=1Cl.[CH:20]([Mg]Cl)([CH3:22])[CH3:21].[Li+].[Cl-].C1COCC1.Cl[C:33](=[O:38])[C:34]([O:36][CH3:37])=[O:35]>[Cu]Br.C1COCC1>[Cl:18][C:14]1[CH:13]=[C:12]([C:10]2[CH:11]=[C:5]3[N:4]=[C:3]([CH3:19])[C:2]([C:33](=[O:38])[C:34]([O:36][CH3:37])=[O:35])=[C:7]([CH:20]([CH3:22])[CH3:21])[N:6]3[N:9]=2)[CH:17]=[CH:16][CH:15]=1
Reactant: Cc1nc2cc(-c3cccc(Cl)c3)nn2c(Cl)c1Br
Reactant: CC(C)[Mg]Cl
Reactant: COC(=O)C(=O)Cl
Agent: [Cu]Br
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)C(=O)c1c(C)nc2cc(-c3cccc(Cl)c3)nn2c1C(C)C
Reaction time: 1 h
Yield: 14.7 %

Procedure:
A 100 mL RB-flask was charged with 6-bromo-7-chloro-2-(3-chlorophenyl)-5-methylpyrazolo[1,5-a]pyrimidine (0.918 g, 2.57 mmol) and copper(I) bromide (0.092 g, 0.643 mmol) was added anhydrous THF (30 mL). To the resulting mixture was added 1M iPrMgCl—LiCl/THF (3.34 ml, 3.34 mmol) over 5 min. After 1 h, methyl 2-chloro-2-oxoacetate (0.501 ml, 5.45 mmol) was added at once to the dark reaction mixture and stirred for additional 1 h. Then, the resulting homogeneous orange brown reaction mixture was quenched with sat NaHCO3 (1 mL), diluted with Et2O (75 mL), washed with water (2×25 mL), brine (25 mL), dried (Na2SO4/C), filtered and concentrated to give yellow residue. This residue was purified on silica gel column using 5-30% EtOAc/Hex (5% increment per 500 mL) to give methyl 2-(2-(3-chlorophenyl)-7-isopropyl-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-oxoacetate (0.1402 g, 0.377 mmol, 14.67% yield) as yellow solid; 1H NMR (500 MHz, CDCl3) δ: 8.01-7.98 (m, 1H), 7.87 (dt, J=7.0, 1.7 Hz, 1H), 7.43-7.38 (m, 2H), 6.87 (s, 1H), 3.98 (s, 3H), 3.43-3.34 (m, 1H), 2.47 (s, 3H), 1.62 (d, J=7.0 Hz, 6H). LCMS (M+H) calcd for C17H16N3O2: 372.11. found: 372.2.
Reaction SMILES: [C:1](OCC)(OCC)(OCC)[CH2:2][CH2:3][CH3:4].[CH3:14][S:15]([CH2:18][CH2:19][O:20][CH2:21][CH2:22][NH:23][C:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[N:27]=[CH:26][C:25]=1[NH2:34])(=[O:17])=[O:16].Cl.N1C=CC=CC=1>C(#N)C>[CH3:14][S:15]([CH2:18][CH2:19][O:20][CH2:21][CH2:22][N:23]1[C:24]2[C:33]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[N:27]=[CH:26][C:25]=2[N:34]=[C:1]1[CH2:2][CH2:3][CH3:4])(=[O:17])=[O:16]
Reactant: CS(=O)(=O)CCOCCNc1c(N)cnc2ccccc12
Reactant: CCCC(OCC)(OCC)OCC
Agent: Cl
Solvent: c1ccncc1
Solvent: CC#N
Product: CCCc1nc2cnc3ccccc3c2n1CCOCCS(C)(=O)=O
Reaction time: 0.67 h
Yield: 85.3 %

Procedure:
Triethyl orthobutyrate (2.2 mL, 14 mmol) was added to a stirred solution of N4-{2-[2-(methylsulfonyl)ethoxy]ethyl}quinoline-3,4-diamine (3.6 g, 12 mmol) in acetonitrile (60 mL). Pyridine hydrochloride (0.3 g) was added and the reaction mixture was heated to reflux with the volatiles being collected in a Dean Stark trap. After 40 minutes analysis by TLC indicated that the starting material was consumed. The reaction mixture was concentrated under reduced pressure to provide 3.7 g of 1-{2-[2-(methylsulfonyl)ethoxy]ethyl}-2-propyl-1H-imidazo[4,5-c]quinoline as a white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:19]=[C:18]([Br:20])[CH:17]=[CH:16][C:5]=1[O:6][C:7]1[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=1[C:9]([OH:11])=[O:10])([O-])=O.C(O)C.O>C(O)(=O)C>[NH2:1][C:4]1[CH:19]=[C:18]([Br:20])[CH:17]=[CH:16][C:5]=1[O:6][C:7]1[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=1[C:9]([OH:11])=[O:10]
Reactant: O=C(O)c1ccccc1Oc1ccc(Br)cc1[N+](=O)[O-]
Solvent: O
Solvent: CCO
Solvent: CC(=O)O
Product: Nc1cc(Br)ccc1Oc1ccccc1C(=O)O
Temperature: 75 °C

Procedure:
A mixture of 2-(2-nitro-4-bromophenoxy)benzoic acid (0.6 g, 0.0018 mol) iron powder (0.69 g 0.012 mol), ethanol (46 mL), water (41 mL), and acetic acid (4.6 mL) was heated to 75° C. for 30 minutes. The mixture was filtered and the solvents evaporated to give the crude product which was purified by flash chromatography (silica gel, ethyl acetate/hexane/formic acid) to give the title compound as a white solid. 1H NMR (400 MHz, CDCl3) δ8.09 (dd, 1H), 7.45-7.50 (m, 1H), 7.16-7.26 (m, 1H), 6.99 (d, 1H), 6.84-6.89 (m, 2H), 6.78 (d, 1H), 5.35 (br s, 3H).
Reaction SMILES: F[C:2](F)(F)[C:3](O)=O.S1C2CCNCC=2C=C1C([NH:19][CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][CH2:29][C:30]([OH:32])=[O:31])=[C:24](OCC(O)=O)[CH:23]=1)=O.[F:38][C:39]([F:44])([F:43])[C:40]([OH:42])=[O:41]>C1(OC)C=CC=CC=1>[NH2:19][CH2:20][CH2:21][C:22]1[CH:23]=[CH:24][C:25]([O:28][CH2:29][C:30]([O:32][CH2:2][CH3:3])=[O:31])=[CH:26][CH:27]=1.[F:38][C:39]([F:44])([F:43])[C:40]([O-:42])=[O:41]
Reactant: O=C(O)C(F)(F)F
Reactant: O=C(O)COc1ccc(CCNC(=O)c2cc3c(s2)CCNC3)cc1OCC(=O)O
Solvent: COc1ccccc1
Product: CCOC(=O)COc1ccc(CCN)cc1
Product: O=C([O-])C(F)(F)F
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To the solution of the compound prepared in (b) (2 g) in anisole (3.3 ml) was added trifluoroacetic acid (3 ml), and the mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure. The residue was washed with n-hexane, dissolved in water and lyophilized to give the title compound in the form of a trifluoroacetate.
Reaction SMILES: [CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[NH:6][C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.[H-].[Na+].[CH3:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2([CH3:28])[CH2:27][O:26]2)=[CH:21][N:20]=1.O>CN(C=O)C.CCOC(C)=O>[CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[N:6]([CH2:28][C:25]([C:22]3[CH:21]=[N:20][C:19]([CH3:18])=[CH:24][CH:23]=3)([OH:26])[CH3:27])[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1
Reactant: Cc1ccc(C2(C)CO2)cn1
Reactant: Cc1ccc2[nH]c3c(c2c1)CN(C)CC3
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc2c(c1)c1c(n2CC(C)(O)c2ccc(C)nc2)CCN(C)C1
Temperature: 120 °C
Reaction time: 3 h

Procedure:
A mixture of compound 2,3,4,5-tetrahydro-2,8-dimethyl-1H-pyrido[4,3-b]indole (1.5 g, 7.5 mmol, 1 equiv.) and NaH (252 mg, 10.5 mmol, 1.4 equiv.) in DMF (30 mL) were heated to 120° C. for 1 h. The reaction mixture was cooled to RT and 2-methyl-5-(2-methyloxiran-2-yl)pyridine (2.46 g, 16.5 mmol, 2.2 equiv.) in DMF (17 mL) was added dropwise over 12 min. The temperature was again raised to 120° C. and stirred for 3 h. The reaction mixture was cooled to RT and water (5 mL) was added, diluted with EtOAc (700 mL) and the organic layer was washed with water (3×100 mL) and then with brine, dried over sodium sulfate and concentrated under vacuum. The compound was purified by column chromatography over 230-400 silica gel using a gradient of 10-20% MeOH in EtOAc. Yield: 2.3 g (87%). 1H NMR (DMSO-d6, oxalate salt) δ (ppm): 8.52 (bs, 1H), 7.73-7.71 (d, 1H), 7.31-7.29 (d, 1H), 7.17-7.15 (m, 2H), 6.88-6.86 (d, 1H), 4.34 (bs, 2H), 4.24-4.40 (dd, 2H), 3.47 (bs, 2H), 2.98 (bs, 2H), 2.91 (s, 3H), 2.42 (s, 3H), 2.35 (s, 3H), 1.48 (s, 3H).
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]3[N:15]=[C:14]([CH2:16][CH2:17][CH:18]4[N:24]=[C:23]([NH2:25])[CH2:22][CH2:21][CH2:20][CH2:19]4)[NH:13][C:10]3=[N:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:26][N:27]([CH3:56])[S:28](C1C=CC(C2C=C3N=C(CCC4CCCCC(=S)N4)NC3=NC=2)=CC=1)(=[O:30])=[O:29].N>CO>[NH2:25][C:23]1[CH2:22][CH2:21][CH2:20][CH2:19][CH:18]([CH2:17][CH2:16][C:14]2[NH:13][C:10]3=[N:11][CH:12]=[C:7]([C:1]4[CH:2]=[CH:3][C:4]([S:28]([N:27]([CH3:56])[CH3:26])(=[O:30])=[O:29])=[CH:5][CH:6]=4)[CH:8]=[C:9]3[N:15]=2)[N:24]=1
Reactant: CN(C)S(=O)(=O)c1ccc(-c2cnc3[nH]c(CCC4CCCCC(=S)N4)nc3c2)cc1
Reactant: NC1=NC(CCc2nc3cc(-c4ccccc4)cnc3[nH]2)CCCC1
Agent: N
Solvent: CO
Product: CN(C)S(=O)(=O)c1ccc(-c2cnc3[nH]c(CCC4CCCCC(N)=N4)nc3c2)cc1

Procedure:
The title compound is synthesized as described for 7-[2-(6-phenyl-3H-imidazo[4,5-b]pyridin-2-yl)-ethyl]-4,5,6,7-tetrahydro-3H-azepin-2-ylamine (compound 1) from 50 mg of N,N-dimethyl-4-{2-[2-(7-thioxo-azepan-2-yl)-ethyl]-3H-imidazo[4,5-b]pyridin-6-yl}-benzenesulfonamide (compound A5) and 2.53 ml of methanol containing ammonia (strength: 7.0 M) at 50° C. for 65 hours. Purification by flash chromatography on LiChroprep-NH2® (eluent: dichloromethane/0-10 vol. % methanol) and lyophilisation from dioxane/water (10:1 parts by volume) afford 32 mg of the title compound as an amorphous, colorless solid of m.p. 195° C. (decomp.). ESI-MS: 441.2 (MH+). TLC: Rf=0.44 (LiChroprep-NH2® HPTLC, methanol/water 10:1 parts by volume).
Reaction SMILES: [OH:1][C:2]1([C:21]#N)[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[N:16]=[N:17][N:18]([CH3:20])[N:19]=3)=[CH:11][CH:10]=2)[CH2:4][CH2:3]1.Cl.[OH-:24].[Na+].[CH2:26]([OH:28])[CH3:27]>>[OH:1][C:2]1([C:21]([O:28][CH2:26][CH3:27])=[O:24])[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[N:16]=[N:17][N:18]([CH3:20])[N:19]=3)=[CH:11][CH:10]=2)[CH2:4][CH2:3]1
Reactant: CCO
Reactant: [OH-]
Reactant: Cn1nnc(-c2ccc(CN3CCC(O)(C#N)CC3)cc2)n1
Agent: Cl
Agent: [Na+]
Product: CCOC(=O)C1(O)CCN(Cc2ccc(-c3nnn(C)n3)cc2)CC1
Temperature: 55 °C
Reaction time: 20 h

Procedure:
A solution of 9.6 grams (0.032 mole) of 4-hydroxy-1-{[4-(2-methyl(1,2,3,4-tetrazol-5-yl))phenyl]methyl}piperidine-4-carbonitrile in 200 mL of ethanol was saturated with gaseous hydrogen chloride, and then it was stirred at 55° C. for about 20 hours. The reaction mixture was allowed to cool and then it was poured onto 500 mL of ice. The resultant mixture was basified with 50% sodium hydroxide and extracted once with 300 mL of ethyl acetate. The extract was washed three times with 80 mL brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure to a residue, yielding 5.14 grams of the subject compound. The NMR spectrum was consistent with the proposed structure.